This project will investigate the role of the hippocampus and related medial temporal lobe (MTL) structures in sequence memory. These studies are guided by our recent findings with functional magetic resonance imaging (fMRI) indicating that the human hippocampus is activated in early stages of sequence learning (Schendan et a)., 2003), and also our recent animal and modeling studies that suggest the hippocampus is critical in memory for temporal order (Fortin et al., 2002), and for the disambiguation of overlapping sequences of events in memory (Sohal and Hasselmo, 1998;Agster et al., 2002). The proposed project has three specific aims. The first aim is to use fMRI to explore the scope of hippocampal involvement in sequence learning in humans. Experiments 1 and 2 will examine hippocampal, parahippocampal, prefrontal, and striatal activity during the encoding, delay, and retrieval components of encoding tasks that will contrast learning and memory performance for items, sequences of items, and spatial context information. These event-related fMRI studies directly parallel studies that have been and will be carried out in animal models. Our hypothesis is that the hippocampus is critical not only for associative and contextual learning, but also for remembering the order of events in unique experiences. We further predict that perirhinal activity will relate to item learning, but not contextual or sequence learning. The second aim is to use fMRI to explore the role of the hippocampus in sequence disambiguation. Experiments directly parallel studies in animal models (Agster et al., 2002;Wood, et al, 2000). Exp. 3 will examine hippocampal activation in encoding overlapping versus non-overlapping non-spatial sequences. Exp. 4 is the spatial analog of Exp. 3, and will examine navigation through virtual reality mazes using overlapping and non-overlapping paths. The third aim is to use fMRI to contrast the medial temporal lobe, prefrontal, and striatal systems in sequence learning. Exp. 5 examines implicit sequence learning in a sequence embedded in a "prefrontal" N-back task. Exp. 6 examines learning of first order (FOG) or second order conditional (SOC) sequences in an incidental picture encoding task. The prediction is that FOG sequences will activate the striatum but not the MTL, whereas SOC sequences will activate the MTL. The combined studies will provide a hypothesis-driven examination of episodic sequence learning that closely parallels the studies and models proposed.